The Antithrombogenic In Vivo Effects of Calcium Channel Blockers in Experimental Thrombosis in Mice

Summary

A new model of thrombotic challenge, well suited for screening agents and which acts primarily against platelet thromboembolism, has been used to test the in vivo anti-platelet effects of four calcium channel blockers (CCB). An i. v. injection of a mixture of collagen plus epinephrine (15 μg and 1.8 μg/mouse, respectively) was given to male mice. 94% control mice died or remained paralyzed for more than 15 minutes. The dihydropyridine agents, CRE-223 and Nifedipine, were highly protective against experimental thrombosis, whereas Verapamil had a weaker and much shorter effect and, on the other hand, Diltiazem had no protective effect over a range of doses. The activity on both dihydropyridines lasted for seven hours or even longer.

Keywords

Calcium channel blockers - Antithrombotic agents - Thrombosis model - Dihydropyridines - Verapamil - Diltiazem

• References

• 1 Vargaftig BB, Chignard M, Benveniste J. Present concepts of the mechanism of platelet aggregation. Biochem Pharmacol 1981; 30: 263-271
• 2 Le Breton GC, Owen NE, Feinberg H. Relationship of cyclic nucleotides and calcium in platelet function. In Calcium regulation by calcium antagonist. p. 153 Rahwan RG, Witiak DT. (ed.). ACS Symposium Series; 1982
• 3 Owen NE, Feinberg H, LeBreton GC. Epinephrine induces Ca⁺⁺ uptake into human blood platelet. Am J Physiol 1980; 239: H483-H488
• 4 Owen NE, LeBreton GC. Ca⁺⁺ mobilization in blood platelet as visualized by chlortetracycline fluorescence. Am J Physiol 1981; 241: H613-H619
• 5 Godfraind T. Mechanism of action of Calcium entry Blockers. Fed. Proc. 1981; 40: 2866-2871
• 6 Braunwald E. Mechanism of action of Calcium Channel Blocking Agents. New Engl J Med 1982; 307: 1618-1627
• 7 Ono H, Kimura M. Effect of Ca⁺⁺ antagonistic vasodilators, Diltiazem, Nifedipine, Perhexiline and Verapamil on platelet aggregation in vitro. Arzneim. Forsch/Drug Res. 1981; 31: 1131-1134
• 8 Han P, Boatwright C, Ardlie NG. Effect of the calcium-entry blocking agent Nifedipine on activation of human platelets and comparison with Verapamil. Thromb Haemostas 1983; 50: 513-517
• 9 DiMinno G, Silver MJ. Mouse antithrombotic assay: A simple method for the evaluation of anti-thrombotic agents in vivo. Potentiation of antithrombotic activity by ethyl alcohol. H Pharmacol Exptl Ther dto 1983; 225: 57-60
• 10 Nishizawa E, Wynalda DJ, Suydam DE, Sawa TR, Schultz JR. Collagen-induced pulmonary thromboembolism in mice. Thromb. Res 1972; 1: 233-242
• 11 Silver MJ. Mechanism of hemostasis and therapy of thrombosis: New concepts based on the metabolism of arachidonic acid by platelets and endothelial cells. Adv. Pharmacol. Chemother. 1981; 18: 1-47
• 12 Ikeda Y, Kikuchi M, Toyama K, Watanabe K, Ando Y. Inhibition of human platelet functions by Verapamil. Thromb Haemostas 1981; 45: 158-161
• 13 Kirchberger MA, Tada M, Katz AM. Adenosin 3’-5’-monophosphate-dependent proteinkinase-catalyzed phosphorylation reaction and its relationship to calcium transport in cardiac sarcoplasmic reticulum. J. Biol. Chem. 1974; 249: 6166-6173
• 14 Diyle VM, Riiegg UT. Lack of evidence for voltage dependent calcium channels on platelets. Biochem. Biophys. Res. Comm. 1985; 127: 161-167
• 15 Onoda JM, Sloane BF, Honn KV. Antithrombogenic effects of calcium channel blockers: Synergism with prostacyclin and thromboxane synthase inhibitors. Thromb. Res. 1984; 34: 367-378
• 16 Srivastava KC, Awasthi KK. Arachidonic acid metabolism in isolated aorta and lung of rat: Effects of Dipyridamole, Nifedipine, Propranolol, Hydralazine and Verapamil. Prostaglan Leukot Med 1983; 10: 411-421
• 17 Feinstein MB, Fiekers J, Fraser C. An analysis of the mechanism of local anesthetic inhibition of platelet aggregation and secretion. J. Pharmacol. Exptl Ther 1976; 197: 215-228
• 18 Triggle DJ. Chemical Pharmacology of Calcium Antagonists, in Calcium regulation by calcium antagonist. Ed. Rahwan RG, Witiak DT. ACS Symposium Series; 1982. 102 17-37